Chlamydia pneumoniae (TWAR) is a common human respiratory pathogen. In recent years, there has been mounting evidence showing that this organism might play a role in atherosclerosis. Because coronary heart disease is a leading cause of death in this country, the overall goal is to investigate the immunopathogenic mechanisms by which C. pneumoniae infection contributes to the development of vascular disease. The proposed studies will exploit our recent findings from mouse model studies linking C. pneumoniae infection and atherosclerosis and in vitro cell culture studies on C. pneumoniae infection of arterial wall cells. The mouse models that will be used are C57BU6 and strains derived from this background strain including, apoE-deficient and TNF-A receptor and apoE double knockout mice. Atherosclerosis in C57BU6 mice can be induced by feeding with a high fat/high cholesterol diet, while apoE mice develop atherosclerosis spontaneously on a regular diet.
The specific aims are to 1) further evaluate the synergistic effect of C. pneumoniae infection and hyperlipidemia on atherogenesis by infecting mice with C. pneumoniae followed by feeding animals with a high fat/high cholesterol diet and measuring the atherosclerotic lesion development using computer assisted morphometry; 2) study the effects of C. pneumoniae infection on key components in the inflammatory process of atherosclerosis that promote atherosclerotic lesion development by recruiting lymphocytes/macrophages and eliciting inflammatory responses at lesion sites. In vitro, in vivo, and ex vivo systems will be used to assay the expression of leukocyte adhesion molecules and adherence of macrophages to the endothelial surface. The effect of TNF-A on lesion development will be investigated by infecting TNF-A receptor and apoE double knockout mice and measuring lesion development using computer assisted morphometry; 3) assess the role of macrophages in the establishment of persistent C. pneumoniae infection of atheromatous lesions using cell culture to analyze vascular cell interactions and the effect on infectivity, growth and persistence of C. pneumoniae, and characterize the growth of C. pneumoniae in macrophages loaded with low density lipoproteins (foam cells). The proposed studies should prove invaluable for understanding the disease process and developing better measures for eradication or prevention of C. pneumoniae infection and for reducing atherosclerosis and coronary heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056036-06
Application #
6537252
Study Section
Special Emphasis Panel (ZRG1-TMP (02))
Program Officer
Tolunay, Eser
Project Start
1997-04-01
Project End
2004-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
6
Fiscal Year
2002
Total Cost
$365,976
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Public Health
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Campbell, Lee Ann; Yaraei, Kambiz; Van Lenten, Brian et al. (2010) The acute phase reactant response to respiratory infection with Chlamydia pneumoniae: implications for the pathogenesis of atherosclerosis. Microbes Infect 12:598-606
Jiang, Shinn-Jong; Campbell, Lee Ann; Berry, Mark W et al. (2008) Retinoic acid prevents Chlamydia pneumoniae-induced foam cell development in a mouse model of atherosclerosis. Microbes Infect 10:1393-7
Jiang, Shinn-Jong; Kuo, Cho-Chou; Berry, Mark W et al. (2008) Identification and characterization of Chlamydia pneumoniae-specific proteins that activate tumor necrosis factor alpha production in RAW 264.7 murine macrophages. Infect Immun 76:1558-64
Takaoka, Naohisa; Campbell, Lee Ann; Lee, Amy et al. (2008) Chlamydia pneumoniae infection increases adherence of mouse macrophages to mouse endothelial cells in vitro and to aortas ex vivo. Infect Immun 76:510-4
Yaraei, Kambiz; Campbell, Lee Ann; Zhu, Xiaodong et al. (2005) Effect of Chlamydia pneumoniae on cellular ATP content in mouse macrophages: role of Toll-like receptor 2. Infect Immun 73:4323-6
Blessing, E; Campbell, L A; Rosenfeld, M E et al. (2005) A 6 week course of azithromycin treatment has no beneficial effect on atherosclerotic lesion development in apolipoprotein E-deficient mice chronically infected with Chlamydia pneumoniae. J Antimicrob Chemother 55:1037-40
Campbell, Lee Ann; Nosaka, Tadayoshi; Rosenfeld, Michael E et al. (2005) Tumor necrosis factor alpha plays a role in the acceleration of atherosclerosis by Chlamydia pneumoniae in mice. Infect Immun 73:3164-5
Yaraei, Kambiz; Campbell, Lee Ann; Zhu, Xiaodong et al. (2005) Chlamydia pneumoniae augments the oxidized low-density lipoprotein-induced death of mouse macrophages by a caspase-independent pathway. Infect Immun 73:4315-22
Puolakkainen, Mirja; Campbell, Lee Ann; Lin, Tsun-Mei et al. (2003) Cell-to-cell contact of human monocytes with infected arterial smooth-muscle cells enhances growth of Chlamydia pneumoniae. J Infect Dis 187:435-40
Chesebro, Brian B; Blessing, Erwin; Kuo, Cho-Chou et al. (2003) Nitric oxide synthase plays a role in Chlamydia pneumoniae-induced atherosclerosis. Cardiovasc Res 60:170-4

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